Somatostatin is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G-protein coupled receptors that results in the inhibition of release of several secondary hormones, including growth hormone and thyroid-stimulating hormone (TSH) in the anterior pituitary; gastrin, cholecystokinin, motilin, glucagon, secretin, pancreatic polypeptide, thyroid stimulating hormone (TSH), gastric inhibitory peptide (GIP), enteroglucagon, and vasoactive intestinal peptide (VIP) in the gastrointestinal system; and insulin and glucagon in the pancreas.

Several synthetic analogs of somatostatin are known, including octreotide, lanreotide, and pasireotide.
Octreotide (D-phenylalanyl-L-cysteinyl-L-phenylalanyl-D-tryptophyl-L-lysyl-L-threonyl-N-[2-hydroxy-1-(hydroxymethyl)propyl]-L-Cysteinamide, cyclic (2→7)-disulfide; [R—(R*,R*)]) is a synthetic octapeptide mimic of the natural peptide somatostatin. It inhibits the secretion of many hormones, including gastrin, cholecystokinin, glucagon, growth hormone, insulin, secretin, pancreatic polypeptide, thyroid stimulating hormone (TSH), and vasoactive intestinal peptide (VIP). It decreases gastric motility, inhibits contraction of the gallbladder, reduces fluid secretion by the intestines and pancreas, causes vasoconstriction, and reduces portal pressures in bleeding varices. It has been shown to produce analgesic effects, possibly through activity at the mu-opioid receptor. The acetate salt has been approved for use in the USA as an injectable depot formulation for treatment of acromegaly, gigantism, thyrotropinoma, diarrhea and flushing associated with carcinoid syndrome, and diarrhea in patients suffering from VIP-secreting tumors. It has been used off-label for treatment of a number of afflictions, including severe refractory diarrhea, prolonged recurrent hypoglycemia after sulfonylurea overdose, insulin hypersecretion in infants with nesidioblastosis, hypertrophic pulmonary osteoarthropathy secondary to non-small cell lung cancer, malignant bowel obstruction, and chronic hypotension.

Octreotide has been used experimentally in the treatment of obesity, chronic pain resulting from pancreatitis, thymic neoplasms, and idiopathic intracranial hypertension.
It has been noted that octreotide alters the balance between the counter-regulatory hormones insulin, glucagon, and growth hormone, and so may cause hypo- or hyper-glycemia. This was observed in acromegalic patients (3% and 16%, respectively), but only at 1.5% in other patient populations.
An immediate-release formulation known as Sandostatin® Injection (Novartis) is self-administered 2 to 4 times daily by subcutaneous injection. Each dose comprises 50, 100, or 500 ug of octreotide acetate formulated with lactic acid, mannitol, and sodium bicarbonate in water at pH 4.2. Initial doses of 50 ug may be upwardly titrated depending on need. After injection of a 100 ug dose, peak concentrations of 5.2 ng/mL were reached. Octreotide is absorbed quickly after subcutaneous administration, and is eliminated from the plasma with an average half-life of 1.7 h; the duration of action is variable but extends up to 12 h.
A microsphere formulation known as Sandostatin LAR® Depot comprises octreotide acetate and mannitol encapsulated in a poly(D,L-lactide-co-glycolide) (PLGA) glucose star polymer, in strengths of 10, 20, or 30 mg of octreotide acetate. The suspension resulting from dilution of the dry microspheres with aqueous carboxymethylcellulose sodium and mannitol is given by a trained health care provider as a monthly intragluteal injection using a 1.5-2″ 19 gauge needle. The microspheres degrade over time through hydrolysis of the copolymer matrix, releasing the octreotide. As the microspheres are unstable in water, the suspension must be carefully prepared and administered immediately after mixing. With multiple monthly dosing, a steady-state level of free octreotide is attained after 3 doses. Dosing 20 mg results in trough levels of 1.2 ng/mL and peak levels of 1.6 ng/mL; dosing 30 mg results in trough levels of 2.1 ng/mL and peak levels of 2.6 ng/mL. Extensive degradation of octreotide in Sandostatin LAR® due to amine acylation by polymer units has been reported (Ghassemi, et al., “Controlled Release of Octreotide and Assessment of Peptide Acylation from Poly(D,L-lactide-co-hydroxymethyl glycolide) Compared to PLGA Microspheres,” Pharm. Res. (2012) 29:110-120). The low pH environment inside PLGA microspheres appears to be detrimental to peptide stability, and thus limits their use as long-term delivery agents for peptides.
Liquid crystal phase depot formulations of octreotide have been recently reported, for example in PCT Publication WO2013/083459 A1 and Boyd, et al., “Lyotropic liquid crystalline phases formed from glycerate surfactants as sustained release drug delivery systems,” Int. J. Pharm. (2006) 309:218-226. Formulations having octreotide non-covalently entrapped within a hydrogel matrix and which may be delivered via a subcutaneous implant have also been disclosed (for example, in U.S. Pat. Nos. 7,803,773 and 7,960,335).
Lanreotide ([3-(2-naphthyl)-D-alanyl-L-cysteinyl-L-tyrosyl-D-tryptophyl-L-lysyl-L-valyl-L-cysteinyl-L-threoninamide cyclic (3→7)-disulfide) has a longer half-life after administration, and is available in two formulations, Somatuline® LA requiring intramuscular injection every 10-14 days and Somatuline® Depot (Somatuline® Autogel in the UK) that is administered deep subcutaneous once a month. Somatuline® Depot comprises lanreotide acetate in supersaturated aqueous semisolid formulation at 60, 90, or 120 mg. Upon deep intramuscular injection, it is thought to form a precipitated drug depot that slowly releases lanreotide with a half-life of 23-30 days. At steady-state after multiple dosing, the mean trough concentrations were 1.8, 2.5, and 3.8 ng/mL at 60, 90, and 120 mg doses, and mean peak concentrations were 3.8, 5.7, and 7.7 ng/mL.

Pasireotide ((2-aminoethyl) carbamic acid (2R,5S,8S,11S,14R,17S,19aS)-11-(4-aminobutyl)-5-benzyl-8-(4-benzyloxybenzyl)-14-(1H-indol-3ylmethyl)-4,7,10,13,16,19-hexaoxo-17-phenyloctadecahydro-3a,6,9,12,15,18-hexaazacyclopentacyclooctadecen-2-yl ester, di[(S)-2-aminosuccinic acid] salt) is an orphan drug approved in the U.S. and Europe for the treatment of Cushing's disease in patients who fail or are ineligible for surgical therapy. It has a 40-fold increased affinity to somatostatin receptor 5 than other somatostatin analogs.

Pasireotide is marketed as Signifor® (Novartis) in a formulation comprising pasireotide diaspartate at 0.3, 0.6, or 0.9 mg, mannitol, tartaric acid, and water at pH 4.2. Upon subcutaneous administration, it shows a large volume of distribution (>100 L) and an effective half-life of approximately 12 h.
Formulations that have been used for other drugs and that are related to the problems solved in the present invention have been disclosed, for example, in U.S. Pat. No. 8,640,315 which describes linkers wherein the drug is bound to a system for β-elimination through a linkage of the formula —X—C(O)-D, where D is the drug, and the linker couples the drug to a macromolecule.
U.S. Pat. No. 8,754,190 alters the formulation for coupling the drug to that of the formula —O—C(O)—N(B)—CH2-D where, again, D represents a drug and the drug is coupled through a β-elimination linker to a macromolecule.
WO2011/140392 describes similar linkers using both of the aforementioned types of coupling to the drug to link the drug to a solid support. U.S. Pat. No. 8,703,907 uses both types of linkage to the drug to couple the drug through a linker to a dendrimer.
WO2013/036847 describes similar linkages where the linker is coupled to an optionally crosslinked hydrogel. None of these delivery systems is designed specifically to be adapted to appropriate delivery of effective amount of somatostatin or its analogs.
Given the often painful intramuscular or deep subcutaneous injections requiring administration by trained healthcare professionals, and the instability of peptide drugs in PLGA microspheres, there exists a need for improved methods of administering these useful therapeutic agents.